We administered deoxycoformycin (dCF) and interferon-alpha (IFN-alpha) sequentially to patients with hairy cell leukemia in an attempt to improve the response rate and duration observed in earlier studies using each drug alone. Further rationale for this study included the observation that IFN- alpha resistant patients were nearly uniformally responsive to second line dCF. As there was some overlapping toxicity, we decided to administer the drugs sequentially rather than concurrently. In this study, we evaluated patients for response by performing bilateral iliac crest bone marrow biopsies and aspirates since the peripheral blood normalizes rapidly after either IFN-alpha or dCF treatment but disease becomes patchy in the bone marrow and might be missed if only unilateral bone marrow biopsies had been performed. Other studies using IFN-alpha or dCF alone used unilateral marrow examinations in evaluating response. Using these more relaxed criteria of response, authors had published high rates of complete remission to dCF. Of 15 patients entered in our study, 14 are evaluable for response with one patient having diffuse osteosclerosis not being evaluable for marrow response. All patients had rapid normalization of peripheral blood count and all 14 marrow-evaluable patients were found to have very small numbers (less than 5% of the total marrow cellularity) of residual hairy cells at the completion of treatment. Among the 14 evaluable patients, three patients have developed progressive disease off treatment. The single nonevaluable patient with diffuse osteosclerosis developed anemia with increasing serum soluble IL-2 receptor (sIL-2R) levels consistent with progressive hairy cell leukemia. Two patients received treatment with 2-chlorodeoxyadenosine and one received interferon-alpha. Although the initial response rate to the combination of dCF and interferon appears to be no better than that observed with dCF alone, the response duration may be longer. The remaining patients continue to be followed for determination of response duration.